EP0312108B1 - Contrast medium for cancerous growth diagnosis - Google Patents

Contrast medium for cancerous growth diagnosis Download PDF

Info

Publication number
EP0312108B1
EP0312108B1 EP88117158A EP88117158A EP0312108B1 EP 0312108 B1 EP0312108 B1 EP 0312108B1 EP 88117158 A EP88117158 A EP 88117158A EP 88117158 A EP88117158 A EP 88117158A EP 0312108 B1 EP0312108 B1 EP 0312108B1
Authority
EP
European Patent Office
Prior art keywords
medium
vitamins
salts
fluorescein
contrast
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP88117158A
Other languages
German (de)
French (fr)
Other versions
EP0312108A1 (en
Inventor
Nikolai Nikolaevich Dzbanovsky
Viktor Iosifovich Polsachev
Elena Vasilievna Potemkina
Alexandr Tursunovich Rakhimov
Leonid Borisovich Rubin
Alexandr Sergeevich Osipov
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BIO-PHOTONICS Inc
Original Assignee
Bio-Photonics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bio-Photonics Inc filed Critical Bio-Photonics Inc
Publication of EP0312108A1 publication Critical patent/EP0312108A1/en
Application granted granted Critical
Publication of EP0312108B1 publication Critical patent/EP0312108B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations

Definitions

  • the present invention relates to medicine, namely oncology.
  • the present invention can be best and most useful for diagnostics, including early diagnosis of malignant neoplasms, determination of the spread of malignant damage, determination of the scope of operations, clarification of diagnoses in clinics and health care facilities, monitoring of Treatment of malignant tumors and the detection of relapses after surgery are applied.
  • the object of the present invention is to provide a means for contrasting malignant neoplasms, which would ensure high reliability of the diagnosis.
  • the task was unexpectedly solved by the use of contrast agents in addition to fluorescein or its salts or its anion of additives in the form of saccharides and / or disaccharides, vitamins and antihistamines.
  • the mechanism of action of these additives together with the fluorescein is, as far as can be ascertained, as follows.
  • Fluorescein has long been used as a fluorescent dye in biology and medicine. It is well known that fluorescein does not penetrate living cells because its anion has a negative charge that prevents it from penetrating through the cell membrane. It has been unexpectedly found that adding organic acids, which are a product of cell metabolism, to the fluorescent solution causes the fluorescein to begin entering the cells penetrate and accumulate in these by the formation of a complex which neutralizes the charge of the fluorescein anion. This effect was used in the present invention for fluorescence diagnostics. Malignant cells have a glycolytic type of respiration, which is characterized by increased consumption of carbohydrates and deacidification of the interstitial fluid by expelling organic acids as the end product of respiration. As the research has shown, lowering the acidity of the medium leads to the protogenization of fluorescein, to an increase in solubility in cell membranes and consequently to a strong increase in its concentration within malignant cells.
  • the invention relates to an agent for contrasting malignant neoplasms in their diagnosis, containing fluorescein and / or its salts as a contrast substance, which is characterized in that it additionally contains saccharides and / or disaccharides in the following% by weight:
  • An agent of the following composition in% by weight is preferred:
  • the invention further relates to an agent for contrasting malignant neoplasms in their diagnosis containing fluorescein or its salts as a contrast substance, which is characterized in that it additionally contains vitamins in the following% by weight:
  • An agent which contains vitamins in the following ratio in% by weight:
  • the invention further relates to an agent for contrasting malignant neoplasms in their diagnosis, containing fluorescein or its salts as a contrast substance, which is characterized in that it additionally contains antihistamines in the following% by weight:
  • An agent which contains antihistamines in the following ratio in% by weight is preferred:
  • the invention further relates to an agent for contrasting malignant neoplasms in their diagnosis, containing fluorescein or its salts as a contrast substance, which is characterized in that it additionally contains saccharides and / or disaccharides, vitamins and antihistamines in the following% by weight:
  • agent which contains alkali metal salts as fluorescein salts.
  • agent which contains its ammonium salts as fluorescein salts is also preferred.
  • agent which contains Li, Na and K salts as the alkali metal salts of the fluorescein.
  • an agent that contains glucose and / or fructose as saccharides.
  • agent which contains sucrose as the disaccharides is also preferred.
  • an agent which contains as vitamins the vitamins of group A and / or the vitamins of group B and / or the vitamins of group C and / or P and / or PP and / or E.
  • an agent which contains the vitamins of group B and / or the vitamins of group C and / or P and / or PP and or E as vitamins.
  • an agent containing 3-methyl-9-benzyl-1,2,4-tetrahydrocarboline-naphthalene-1,5-disulfonate hydrochloride of 10- (2-dimethylaminopropyl) phenothiazine, hydrochloride of N-dimethylaminoethyl as the antihistamine -N- (para-chlorobenzyl) aminopyridine or 1-methyl-2 [2- (a-methyl-para-chlorobenzhydryloxy) ethyl] pyrrolidine, 4,9-dihydro-4 (1-methy! -4 -piperidiny! iden) -1 -OH-benzo [4,5] cyc!
  • ohepta [1,2] thiophene-10-OH hydrochloride of ⁇ -dimethylaminoethyl ether, benzhydrol or quinuklydyl-3-diphenyl-carbinol .
  • agent which is characterized in that it is present as a solution or powder.
  • agent which is characterized in that it contains water or an aqueous 5 to 30% strength solution of the ethyl alcohol as solvent.
  • the carbohydrates chosen are preferably glucose or fructose as monosaccharides and sucrose as disaccharides for specific physiological peculiarities of the organism, e.g. if the patient has diabetes.
  • vitamins namely A-retinol, B i -thiamine, B 2 -riboflavin, B 6 -pyridoxine chloride, P-rutin, E-tocopherol acetate, C-ascorbic acid and PP Nicotinic acid leads to a general stimulation of metabolytic processes, which are necessary for the active transport of fluorescein into malignant cells, in particular glycolysis.
  • antihistamines for example 3-methyl-9-benzyl-1,2,3,4-tetrahydrocarboline-naphthalene-1,5-disulfonate or hydrochloride of 10- (2-dimethylaminopropyl) phenothiazine, hydrochloride of N-dimethyl aminoethyl-N- (para-chlorobenzyl) aminopyridine or 1-methyl-2/2 (a-methyl-para-chlorobenzh-ydryloxy) ethyl / pyrrolidine, 4,9-dihydro-4- (1-methyl-4- piperidinylidene) 1 -OH-benzo / 4,5 / cyclohepta / 1,2 / thiophene-10-OH (hydrofumarate), hydrochloride of the ⁇ -dimethylaminoethyl ether of the benzhydrol or of the quinuklydyl-3-diphenylcarbinol is due to
  • the preferred composition is as follows:
  • the preferred composition is as follows:
  • the preferred composition is as follows:
  • the preferred composition is as follows:
  • the effective agent in the contrast medium is fluorescein anion, which, being in the patient's blood, is transported through the tissues and accumulates in malignant neoplasms.
  • fluorescein anion either in the contrast medium according to the invention the fluorescein or its salts, preferably the salts of the alkali metals or ammonium, which dissociate in an alkaline medium to form the fluorescein anion.
  • the agents according to the invention can be introduced by intravenous injections, enterally or via the anus. There are also other variants: you can e.g. take the vitamins and carbohydrates enterally and introduce the fluorescein or its salts intravenously.
  • contrast medium can be used either in the form of a uniform solution or a powder or individually in the form of individual solutions or in solid form.
  • Water or a 5 to 30% aqueous ethanolic solution can be used as a solvent for the contrast agent in its entirety or for its individual components. You can also add salts and acids to create an optimal acidity of the medium, as well as flavorings.
  • the solvent can be used either together with the agent (agent in the form of a solution) or separately (agent in the form of a powder plus solvent).
  • the determination of the ability of the fluorescein or its salts to accumulate in malignant cells and tumors was carried out on cell cultures of the He, La, STS and IG fibroblasts, which are cultivated according to standard methods. After the fluorescein or its salts, along with the other components of the agent, had been added to the cell culture and incubated within a few hours, a cell fraction was excreted and, after washing in the cells, the concentration of the dye was determined using the methods of chromatographic and fluorescent analysis.
  • mice CBA, C-57 Black and BALB-C with inoculated tumors carciona cervis, Lewis tumor, carciona intestinum crassum were tested. After a certain time after the introduction of the fluorescein or its salts along with the other components of the agent, the animals were killed under anesthesia and the concentration of the dye in the tumor and in normal tissues was determined. The accumulation contrast was determined as the ratio of the concentrations in the malignant tissue to the normal tissue.
  • Tables 1 to 4 show results of the experiments on mice of the CBA line with uterine cancer vaccinated on the thigh with the determination of the accumulation contrast of the fluorescein in the malignant tumor in comparison to the normal surrounding tissue as a function of the composition of the contrast medium.
  • the malignant elements present in the blood accumulate the fluorescein or its salts and can be discovered under the microscope after the fluorescence contrasting.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pyrane Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Description

Die vorliegende Erfindung bezieht sich auf die Medizin, und zwar auf die Onkologie.The present invention relates to medicine, namely oncology.

Am besten und sinnvollsten kann die vorliegende Erfindung für die Diagnostik, darunter auch für eine frühe Diagnostik von bösartigen Neubildungen, für die Bestimmung der Verbreitung von bösartigen Schädigungen, die Bestimmung des Umfangs von Operationen, die Präzisierung von Diagnosen in Kliniken und Gesundheitsfürsorgestellen, die Überwachung der Behandlung von bösartigen Geschwulsten und die Feststellung von Nachoperationsrückfällen angewendet werden.The present invention can be best and most useful for diagnostics, including early diagnosis of malignant neoplasms, determination of the spread of malignant damage, determination of the scope of operations, clarification of diagnoses in clinics and health care facilities, monitoring of Treatment of malignant tumors and the detection of relapses after surgery are applied.

Gegenwärtig stellt das Problem, bösartige Neubildungen, insbesondere im Frühstadium, zu diagnostizieren, eines der aktuellsten Probleme in der Onkologie dar. Trotz einer weiten Anwendung von histologischen Methoden der Analyse, den großen Erfolgen der Ultraschall- und Röntgendiagnostik, der Endoskopieuntersuchungen sowie der Röntgen- und der NMR-Tomogragrafie sind die Empfindlichkeit, die Genauigkeit und Zugänglichkeit dieser Methoden nicht ausreichend. Eine der Richtungen für die Vervollkommnung der Diagnostik von bösartigen Geschwulsten besteht in der Anwendung von darin selektiv akkumulierten konstrastierenden Stoffen. Es ist z.B. gut bekannt, daß bösartige Geschwulste einige Farbstoffe in einer erhöhten Konzentration im Vergleich zu den normalen Geweben akkumulieren, was für eine Fluoreszenzdiagnostik von Geschwulsten nach einer charakteristischen Fluoreszenz des darin akkumulierten Farbstoffes angewendet wird.The problem of diagnosing malignant neoplasms, particularly in the early stages, is currently one of the most current problems in oncology. Despite the widespread use of histological methods of analysis, the great success of ultrasound and X-ray diagnostics, endoscopic examinations, and X-ray and The sensitivity, accuracy and accessibility of these methods are not sufficient in NMR tomography. One of the directions for the perfection of the diagnosis of malignant tumors is the use of contrasting substances selectively accumulated therein. It is e.g. well known that malignant tumors accumulate some dyes in an increased concentration compared to normal tissues, which is used for fluorescence diagnosis of tumors after a characteristic fluorescence of the dye accumulated therein.

Für eine Fluoreszenzkontrastierung hat man verschiedene Verbindungen, z.B. Antibiotica der Gruppe Tetracyclin, angewendet. Eine Methode gestattete es, den Magenkrebs im Spätstadium (11. und IV. Stadium) festzustellen, jedoch mit einer Genauigkeit, die für diagnostische Zwecke nicht ausreichend war (s. Klinger 1., Katz K., Gastroenterology, 1961, 41, 29-32). Die Anwendung der Endoskopietechnik in Kombination mit der Tetracyclin-Fluoreszenzkontrastierung (s. Barskij I. Ja., Papajan G.W., Tschedrunow W.W., Gluchin JU.A., Sammelband "Lumineszenzanalyse in medizinisch-biologischen Erforschungen", Riga, 1983, Seiten 182-189) zeigte ebenfalls eine nicht ausreichend hohe Zuverlässigkeit der Diagnostik von Geschwulsten durch einen niedrigen Akkumulierungskontrast von Tetracyclin in bösartigen Geweben im Vergleich zu den normalen Geweben.There are various compounds for fluorescence contrasting, e.g. Antibiotics from the tetracycline group. One method made it possible to determine gastric cancer in the late stage (11th and 4th stages), but with an accuracy that was not sufficient for diagnostic purposes (see Klinger 1, Katz K., Gastroenterology, 1961, 41, 29- 32). The application of endoscopy technology in combination with tetracycline fluorescence contrasting (see Barskij I. Ja., Papajan GW, Tschedrunow WW, Gluchin JU.A., anthology "Luminescence analysis in medical-biological research", Riga, 1983, pages 182-189 ) also showed insufficient reliability of tumor diagnosis due to a low accumulation contrast of tetracycline in malignant tissues compared to normal tissues.

Die Fluoreszenzkontrastierung durch den Farbstoff Fluoreszein wurde für die Feststellung von Metastasen in regionären Lymphknoten beim Kehlkopfkrebs angewendet (s. S.I. Mostowoj, Zeitschrift von Ohren-, Nasen- und Halskrankheiten, 1961, Nr. 4, Seiten 34-36). Es wurde hervorgehoben, daß eine helle Fluoreszenz nicht nur durch den Krebsvorgang geschädigte Lymphknoten, sondern auch andere Organe aufwiesen, was diese Methode für die Diagnostik unbrauchbar machte. Zu Analogieschlüssen sind auch die Autoren einer Reihe von anderen Arbeiten gekommen (s. Moore G.E. Science 1947, 106, 130-131, Figge F.H.I., Weinland G.S., Maganiello L.O.I., Proc. Soc. Exper. Biol. Med. 68, 640-641, 1948).The fluorescence contrast with the dye fluorescein was used for the detection of metastases in regional lymph nodes in laryngeal cancer (see S.I. Mostowoj, Journal of Ear, Nose and Throat Diseases, 1961, No. 4, pages 34-36). It was emphasized that bright fluorescence showed not only lymph nodes damaged by the cancer process, but also other organs, which made this method unusable for diagnostics. The authors of a number of other papers have also come to analogy conclusions (see Moore GE Science 1947, 106, 130-131, Figge FHI, Weinland GS, Maganiello LOI, Proc. Soc. Exper. Biol. Med. 68, 640-641 , 1948).

Man hat auch versucht, ein Mittel zur Kontrastierung von bösartigen Geschwulsten zu entwickeln, welches als Kontrastierungsstoff das Fluoreszein enthielt. Dieses wurde entweder als 20%ige Lösung (2 bis 5 ml für eine intravenöse Einführung) oder in Form eines Pulvers (1 g), auf welches Sodawasser getrunken wurde, angewendet ( s. Ju.N. Efuni, Zeitschrift "Vestnik otorinolaringologii", 1961, Nr. 2, Seiten 11-15). Ein Nachteil dieses Kontrastmittels ist ein niedriger Kontrast der Akkumulierung von Fluoreszein in einem bösartigen Gewebe im Vergleich zu einem normalen Gewebe, was die Genauigkeit der Diagnostik verringert. Der Akkumulierungskontrast des Fluoreszeins in der bösartigen Geschwulst im Vergleich zum normalen Gewebe wurde durch ein Verhältnis der Konzentration des darin enthaltenen Fluoreszeins pro Gramm der Masse des Gewebes bestimmt. Nach den Literaturangaben betrug die Richtigkeit der Fluoreszenzdiagnostik von bösartigen Geschwulsten, z.B. von Ohren-, Nasen- und Halsgeschwulsten, 30 %. Man kam zu dem Ergebnis, daß epitheliale bösartige Geschwulste nicht fluoreszieren, d.h. daß sie das Fluoreszein nicht akkumulieren.Attempts have also been made to develop a means for contrasting malignant tumors which contains fluorescein as a contrasting substance. This was used either as a 20% solution (2 to 5 ml for intravenous introduction) or in the form of a powder (1 g) onto which soda water was drunk (see Ju.N. Efuni, magazine "Vestnik otorinolaringologii", 1961, No. 2, pages 11-15). A disadvantage of this contrast agent is a low contrast of the accumulation of fluorescein in a malignant tissue compared to normal tissue, which reduces the accuracy of the diagnosis. The contrast of accumulation of the fluorescein in the malignant tumor compared to normal tissue was determined by a ratio of the concentration of the fluorescein contained per gram of the mass of the tissue. According to the literature, the correctness of the fluorescence diagnosis of malignant tumors, e.g. of ear, nose and throat swellings, 30%. The result was that epithelial malignancies did not fluoresce, i.e. that they don't accumulate the fluorescein.

Die Aufgabe der vorliegenden Erfindung besteht darin, ein Mittel zur Kontrastierung von bösartigen Neubildungen bereitzustellen, welches eine hohe Zuverlässigkeit der Diagnostik gewährleisten würde. Die gestellte Aufgabe wurde unerwartet durch die Anwendung im Mittel zur Kontrastierung neben dem Fluoreszein oder seinen Salzen oder seinem Anion von Zusatzstoffen in Form von Sacchariden und/oder Disacchariden, Vitaminen und Antihistaminica gelöst. Der Wirkungsmechanismus dieser Zusatzstoffe zusammen mit dem Fluoreszein, der im voraus absolut nicht offensichtlich war, besteht, soweit feststellbar, in folgendem.The object of the present invention is to provide a means for contrasting malignant neoplasms, which would ensure high reliability of the diagnosis. The task was unexpectedly solved by the use of contrast agents in addition to fluorescein or its salts or its anion of additives in the form of saccharides and / or disaccharides, vitamins and antihistamines. The mechanism of action of these additives together with the fluorescein, which was absolutely not obvious beforehand, is, as far as can be ascertained, as follows.

Das Fluoreszein wird als ein fluoreszierender Farbstoff in der Biologie und der Medizin schon seit langem angewendet. Es ist allgemein bekannt, daß das Fluoreszein in lebende Zellen nicht durchdringt, weil sein Anion über eine negative Ladung verfügt, welche das Durchdringen durch die Zellmembrane verhindert. Es wurde unerwartet festgestellt, daß, wenn man der Fluoreszenzlösung organische Säuren, welche Produkt des Zellmetabolismus sind, zugibt, dies dazu führt, daß das Fluoreszein beginnt, in die Zellen einzudringen und sich in diesen durch die Bildung eines Komplexes, welcher die Ladung des Fluoreszeinanions neutralisiert, zu akkumulieren. Dieser Effekt wurde in der vorliegenden Erfindung für eine Fluoreszenzdiagnostik benutzt. Bösartige Zellen verfügen über einen glykolytischen Typ der Atmung, für welchen ein erhöhter Verbrauch von Kohlenhydraten und eine Entsäuerung der Zwischengewebeflüssigkeit durch den Auswurf von organischen Säuren als Endprodukt der Atmung charakteristisch sind. Wie die Forschungen gezeigt haben, führt die Senkung des Säuregehaltes des Mediums zur Protenisation des Fluoreszeins, zur Erhöhung der Lösbarkeit in Zellmembranen und folglich zu einer starken Erhöhung seiner Konzentration innerhalb bösartiger Zellen.Fluorescein has long been used as a fluorescent dye in biology and medicine. It is well known that fluorescein does not penetrate living cells because its anion has a negative charge that prevents it from penetrating through the cell membrane. It has been unexpectedly found that adding organic acids, which are a product of cell metabolism, to the fluorescent solution causes the fluorescein to begin entering the cells penetrate and accumulate in these by the formation of a complex which neutralizes the charge of the fluorescein anion. This effect was used in the present invention for fluorescence diagnostics. Malignant cells have a glycolytic type of respiration, which is characterized by increased consumption of carbohydrates and deacidification of the interstitial fluid by expelling organic acids as the end product of respiration. As the research has shown, lowering the acidity of the medium leads to the protogenization of fluorescein, to an increase in solubility in cell membranes and consequently to a strong increase in its concentration within malignant cells.

Gegenstand der Erfindung ist ein Mittel zur Kontrastierung von bösartigen Neubildungen bei ihrer Diagnostik, enthaltend Fluoreszein und/oder seine Salze als Kontraststoff, das dadurch gekennzeichnet ist, daß dieses zusätzlich Saccharide und/oder Disaccharide in folgenden Gew.-% enthält:

Figure imgb0001
The invention relates to an agent for contrasting malignant neoplasms in their diagnosis, containing fluorescein and / or its salts as a contrast substance, which is characterized in that it additionally contains saccharides and / or disaccharides in the following% by weight:
Figure imgb0001

Bevorzugt ist ein Mittel folgender Zusammensetzung in Gew.-%:

Figure imgb0002
An agent of the following composition in% by weight is preferred:
Figure imgb0002

Gegenstand der Erfindung ist ferner ein Mittel zur Kontrastierung von bösartigen Neubildungen bei ihrer Diagnostik enthaltend Fluoreszein oder seine Salze als Kontraststoff, das dadurch gekennzeichnet ist, daß dieses zusätzlich Vitamine in folgenden Gew.-% enthält:

Figure imgb0003
The invention further relates to an agent for contrasting malignant neoplasms in their diagnosis containing fluorescein or its salts as a contrast substance, which is characterized in that it additionally contains vitamins in the following% by weight:
Figure imgb0003

Bevorzugt ist ein Mittel, das Vitamine in folgendem Verhältnis in Gew.-% enthält:

Figure imgb0004
An agent is preferred which contains vitamins in the following ratio in% by weight:
Figure imgb0004

Gegenstand der Erfindung ist ferner ein Mittel zur Kontrastierung von bösartigen Neubildungen bei ihrer Diagnostik, enthaltend Fluoreszein oder seine Salze als Kontraststoff, das dadurch gekennzeichnet ist, daß dieses zusätzlich Antihistaminica in folgenden Gew.-% enthält:

Figure imgb0005
The invention further relates to an agent for contrasting malignant neoplasms in their diagnosis, containing fluorescein or its salts as a contrast substance, which is characterized in that it additionally contains antihistamines in the following% by weight:
Figure imgb0005

Bevorzugt ist ein Mittel, das Antihistaminica in folgendem Verhältnis in Gew.-% enthält:

Figure imgb0006
An agent which contains antihistamines in the following ratio in% by weight is preferred:
Figure imgb0006

Gegenstand der Erfindung ist ferner ein Mittel zur Kontrastierung von bösartigen Neubildungen bei ihrer Diagnostik, enthaltend Fluoreszein oder seine Salze als Kontraststoff, das dadurch gekennzeichnet ist, daß dieses zusätzlich Saccharide und/oder Disaccharide, Vitamine und Antihistaminica in folgenden Gew.-% enthält:

Figure imgb0007
The invention further relates to an agent for contrasting malignant neoplasms in their diagnosis, containing fluorescein or its salts as a contrast substance, which is characterized in that it additionally contains saccharides and / or disaccharides, vitamins and antihistamines in the following% by weight:
Figure imgb0007

Bevorzugtist ein Mittel, das Saccharide und/oder Disaccharide, Vitamine und Antihistaminica in folgendem Verhältnis in Gew.-% enthält:

Figure imgb0008
Preferred is an agent which contains saccharides and / or disaccharides, vitamins and antihistamines in the following ratio in% by weight:
Figure imgb0008

Bevorzugt ist ferner ein Mittel, das als Fluoreszeinsalze Alkalimetallsalze enthält.Also preferred is an agent which contains alkali metal salts as fluorescein salts.

Bevorzugt ist ferner ein Mittel, das als Fluoreszeinsalze seine Ammoniumsalze enthält.Also preferred is an agent which contains its ammonium salts as fluorescein salts.

Bevorzugt ist ferner ein Mittel, das als Alkalimetallsalze des Fluoreszeins Li-, Na- und K-Salze enthält.Also preferred is an agent which contains Li, Na and K salts as the alkali metal salts of the fluorescein.

Bevorzugt ist ferner ein Mittel, das als Saccharide Glukose und/oder Fruktose enthält.Also preferred is an agent that contains glucose and / or fructose as saccharides.

Bevorzugt ist ferner ein Mittel, das als Disaccharide Saccharose enthält.Also preferred is an agent which contains sucrose as the disaccharides.

Bevorzugt ist ferner ein Mittel, das als Vitamine die Vitamine der Gruppe A und/oder die Vitamine der Gruppe B und/ oder die Vitamine der Gruppe C und/oder P und/oder PP und/ oder E enthält.Also preferred is an agent which contains as vitamins the vitamins of group A and / or the vitamins of group B and / or the vitamins of group C and / or P and / or PP and / or E.

Bevorzugt ist ferner ein Mittel, das als Vitamine die Vitamine der Gruppe B und/oder die Vitamine der Gruppe C und/ oder P und/oder PP und oder E enthält.Also preferred is an agent which contains the vitamins of group B and / or the vitamins of group C and / or P and / or PP and or E as vitamins.

Bevorzugt ist ferner ein Mittel, das als Antihistaminica 3-Methyl-9-benzyl-1,2,4-tetrahydrocarbolin- naphthalin-1,5-disulfonat,Hydrochlorid des 10-(2-Dimethylaminopropyl)-phenothiazins, Hydrochlorid des N-Dimethylaminoethyl-N-(para-chlorbenzyl)-aminopyridins oder 1-Methyl-2[2-(a-methyl-para-chlorbenzhydry- loxy)-ethyl]-pyrrolidins, 4,9-Dihydro-4(1 -methy!-4-piperidiny!iden)-1 -OH-benzo[4,5]cyc!ohepta[1,2]thiophen-10-OH(Hydrofumarat), Hydrochlorid des β-Dimethylaminoethylethers des Benzhydrols oder des Chinuklydyl-3-diphenyl-carbinols enthält.Also preferred is an agent containing 3-methyl-9-benzyl-1,2,4-tetrahydrocarboline-naphthalene-1,5-disulfonate, hydrochloride of 10- (2-dimethylaminopropyl) phenothiazine, hydrochloride of N-dimethylaminoethyl as the antihistamine -N- (para-chlorobenzyl) aminopyridine or 1-methyl-2 [2- (a-methyl-para-chlorobenzhydryloxy) ethyl] pyrrolidine, 4,9-dihydro-4 (1-methy! -4 -piperidiny! iden) -1 -OH-benzo [4,5] cyc! ohepta [1,2] thiophene-10-OH (hydrofumarate), hydrochloride of β-dimethylaminoethyl ether, benzhydrol or quinuklydyl-3-diphenyl-carbinol .

Bevorzugt ist ferner ein Mittel, das dadurch gekennzeichnet ist, daß es als Lösung oder Pulver vorliegt.Also preferred is an agent which is characterized in that it is present as a solution or powder.

Bevorzugt ist ferner ein Mittel, das dadurch gekennzeichnet ist, daß es als Lösungsmittel Wasser oder wässerige 5 bis 30%ige Lösung des Ethylalkohols enthält.Also preferred is an agent which is characterized in that it contains water or an aqueous 5 to 30% strength solution of the ethyl alcohol as solvent.

Als Kohlehydrate wählt man vorzugsweise Glukose oder Fruktose als Monosaccharide sowie Saccharose als Disaccharide bei konkreten physiologischen Besonderheiten des Organismus, z.B. wenn der Patient an Diabetes leidet.The carbohydrates chosen are preferably glucose or fructose as monosaccharides and sucrose as disaccharides for specific physiological peculiarities of the organism, e.g. if the patient has diabetes.

Der Zusatz an Vitaminen, und zwar des A-Retinols, des Bi-Thiamins, des B2-Riboflavins, des B6-Pyridoxin-Chlorids, des P-Rutins, E-Tokopherol-Acetats, der C-Ascorbinsäure und der PP-Nikotinsäure führt zu einer allgemeinen Stimulierung von metabolytischen Prozessen, die für den aktiven Fluoreszeintransport in bösartige Zellen erforderlich sind, insbesondere der Glykolyse.The addition of vitamins, namely A-retinol, B i -thiamine, B 2 -riboflavin, B 6 -pyridoxine chloride, P-rutin, E-tocopherol acetate, C-ascorbic acid and PP Nicotinic acid leads to a general stimulation of metabolytic processes, which are necessary for the active transport of fluorescein into malignant cells, in particular glycolysis.

Die Anwendung der Antihistaminica beispielsweise von 3-Methyl-9-benzyl-1,2,3,4-tetrahydrocarbolin- naphthalin-1,5-disulfonat oder Hydrochlorid des 10-(2-Dimethylaminopropyl)-phenothiazins, Hydrochlorid des N-Dimethyl-aminoethyl-N-(para-chlorbenzyl)aminopyridins oder 1-Methyl-2/2(a-methyl-para-chlorbenzh- ydryloxy)-ethyl/-pyrrolidins, 4,9-Dihydro-4-(1 -methyl-4-piperidinyliden)1 -OH-benzo/4,5/cyclohepta/1,2/thiophen-10-OH(hydrofumarat), Hydrochlorid des ß-Dimethylaminoethylethers des Benzhydrols oder des Chinuklydyl-3-diphenylcarbinols ist auf die Verringerung der Geschwindigkeit des Austritts des Fluoreszeins aus den bösartigen Zellen gerichtet. Dabei wird auch die Erhöhung der Konzentration des Fluoreszeins in den bösartigen Zellen gewährleistet und als Folge der positive Effekt, und zwar ein erhöhter Kontrast der Akkumulierung des Fluoreszeins in einem bösartigen Gewebe erreicht. Somit gewährleisten die angewandten Zusatzstoffe sowohl die Erhöhung einer selektiven Akkumulierung des Fluoreszeins als auch die Senkung der Geschwindigkeit seines Austritts aus den Zellen. Es sei hervorzuheben, daß die Selektivität dieses Prozesses, die durch die Besonderheiten des Metabolismus von bösartigen Zellen bedingt ist, sich im ganzen in einem hohen Kontrast der Akkumulierung des Fluoreszeins in bösartigen Geweben im Vergleich zu den normalen Geweben gezeigt hat.The use of the antihistamines, for example 3-methyl-9-benzyl-1,2,3,4-tetrahydrocarboline-naphthalene-1,5-disulfonate or hydrochloride of 10- (2-dimethylaminopropyl) phenothiazine, hydrochloride of N-dimethyl aminoethyl-N- (para-chlorobenzyl) aminopyridine or 1-methyl-2/2 (a-methyl-para-chlorobenzh-ydryloxy) ethyl / pyrrolidine, 4,9-dihydro-4- (1-methyl-4- piperidinylidene) 1 -OH-benzo / 4,5 / cyclohepta / 1,2 / thiophene-10-OH (hydrofumarate), hydrochloride of the β-dimethylaminoethyl ether of the benzhydrol or of the quinuklydyl-3-diphenylcarbinol is due to the reduction in the rate of escape of the Fluoresceins directed from the malignant cells. This also ensures an increase in the concentration of fluorescein in the malignant cells and, as a result, the positive effect, namely an increased contrast in the accumulation of the fluorescein in a malignant tissue. The additives used thus ensure both an increase in the selective accumulation of fluorescein and a decrease in the rate at which it emerges from the cells. It should be emphasized that the selectivity of this process, which is due to the peculiarities of the metabolism of malignant cells, has been shown overall in a high contrast of the accumulation of fluorescein in malignant tissues compared to normal tissues.

Unter Berücksichtigung von individuellen Besonderheiten des Organismus ist es möglich, folgende Varianten des Mittels mit folgender Zusammensetzung (in Gew.-%) anzuwenden:

Figure imgb0009
Taking into account individual peculiarities of the organism, it is possible to use the following variants of the agent with the following composition (in% by weight):
Figure imgb0009

Die bevorzugte Zusammensetzung ist die folgende:

Figure imgb0010
Figure imgb0011
Figure imgb0012
 The preferred composition is as follows:
Figure imgb0010
Figure imgb0011
Figure imgb0012

Die bevorzugte Zusammensetzung ist die folgende:

Figure imgb0013
Figure imgb0014
Figure imgb0015
 The preferred composition is as follows:
Figure imgb0013
Figure imgb0014
Figure imgb0015

Die bevorzugte Zusammensetzung ist die folgende:

Figure imgb0016
Figure imgb0017
 The preferred composition is as follows:
Figure imgb0016
Figure imgb0017

Es sind im Kontrastmittel auch andere Kombinationen der oben aufgezählten Komponenten untereinander möglich. Aus allen möglichen Kombinationen ist folgende volle Zusammensetzung des Mittels (in Gew.-%) bevorzugt:

Figure imgb0018
In the contrast medium, other combinations of the components listed above with one another are also possible. The following full composition of the composition (in% by weight) is preferred from all possible combinations:
Figure imgb0018

Die bevorzugte Zusammensetzung ist folgende:

Figure imgb0019
Figure imgb0020
 The preferred composition is as follows:
Figure imgb0019
Figure imgb0020

Wird eine der Komponenten des Kontrastmittels nach dem oben angeführten Schema ausgeschlossen, senkt sich der Kontrast seiner Akkumulierung in bösartigen Geschwulsten etwas, bleibt aber trotzdem auf einem höheren Niveau im Vergleich zum Stand der Technik (s. Tabellen 1 bis 4).If one of the components of the contrast medium is excluded according to the above-mentioned scheme, the contrast of its accumulation in malignant tumors decreases somewhat, but still remains at a higher level compared to the prior art (see Tables 1 to 4).

Es ist prinzipiell wichtig, daß als wirksames Agens im Kontrastmittel Fluoreszeinanion ist, welches, indem es sich im Blut des Patienten befindet, durch die Gewebe transportiert wird und sich in bösartigen Neubildungen akkumuliert. Im Zusammenhang damit können im erfindungsgemäßen Kontrastmittel entweder Fluoreszein oder seine Salze, vorzugsweise die Salze der Alkalimetalle oder Ammonium, die in einem alkalischen Medium unter Bildung des Fluoreszeinanions dissoziieren, angewendet werden.It is important in principle that the effective agent in the contrast medium is fluorescein anion, which, being in the patient's blood, is transported through the tissues and accumulates in malignant neoplasms. In connection with this, either in the contrast medium according to the invention the fluorescein or its salts, preferably the salts of the alkali metals or ammonium, which dissociate in an alkaline medium to form the fluorescein anion.

Man kann die erfindungsgemäßen Mittel durch intravenöse Injektionen, enteral oder über den Anus einführen. Es gibt auch andere Varianten: man kann z.B. die Vitamine und die Kohlenhydrate enteral einnehmen und das Fluoreszein oder seine Salze intravenös einführen.The agents according to the invention can be introduced by intravenous injections, enterally or via the anus. There are also other variants: you can e.g. take the vitamins and carbohydrates enterally and introduce the fluorescein or its salts intravenously.

Einzelne Komponenten des Kontrastmittels können entweder in Form einer einheitlichen Lösung oder eines Pulvers oder einzeln in Form von individuellen Lösungen oder in fester Form angewendet werden.Individual components of the contrast medium can be used either in the form of a uniform solution or a powder or individually in the form of individual solutions or in solid form.

Als Lösungsmittel für das Kontrastmittel im ganzen oder für seine einzelnen Komponenten kann Wasser oder eine 5 bis 30%ige wässerige ethanolische Lösung angewendet werden. Man kann auch Salze und Säuren zusetzen, um eine optimale Azidität des Mediums zu schaffen, sowie Geschmacksstoffe.Water or a 5 to 30% aqueous ethanolic solution can be used as a solvent for the contrast agent in its entirety or for its individual components. You can also add salts and acids to create an optimal acidity of the medium, as well as flavorings.

Man kann das Lösungsmittel entweder zusammen mit dem Mittel (Mittel in Form einer Lösung) oder getrennt (Mittel in Form eines Pulvers plus Lösungsmittel) anwenden.The solvent can be used either together with the agent (agent in the form of a solution) or separately (agent in the form of a powder plus solvent).

Die Bestimmung der Fähigkeit des Fluoreszeins oder seiner Salze, sich in bösartigen Zellen und Geschwulsten zu akkumulieren, wurde auf Zellkulturen der He-, La-, STS-, der IG-Fibroplaste, welche nach Standardmethoden kultiviert werden, durchgeführt. Nachdem der Zellkultur das Fluoreszein oder seine Salze neben den anderen Komponenten des Mittels zugesetzt und innerhalb von einigen Stunden inkubiert worden waren, wurde eine Zellfraktion ausgeschieden und nach dem Waschen in den Zellen die Konzentration des Farbstoffes unter Anwendung der Methoden einer chromatografischen und einer Fluoreszenzanalyse bestimmt.The determination of the ability of the fluorescein or its salts to accumulate in malignant cells and tumors was carried out on cell cultures of the He, La, STS and IG fibroblasts, which are cultivated according to standard methods. After the fluorescein or its salts, along with the other components of the agent, had been added to the cell culture and incubated within a few hours, a cell fraction was excreted and, after washing in the cells, the concentration of the dye was determined using the methods of chromatographic and fluorescent analysis.

In Versuchen mit Labortieren wurden Mäuse CBA, C-57 Black und BALB-C mit umgeimpften Geschwulsten carciona cervis, Lewis tumor, carciona intestinum crassum getestet. Nach einer bestimmten Zeit nach der Einführung des Fluoreszeins oder seiner Salze neben den anderen Komponenten des Mittels wurden die Tiere unter Narkose getötet und die Konzentration des Farbstoffes in der Geschwulst und in normalen Geweben bestimmt. Der Akkumulierungskontrast wurde als Verhältnis der Konzentrationen im bösartigen Gewebe zum normalen Gewebe bestimmt.In experiments with laboratory animals, mice CBA, C-57 Black and BALB-C with inoculated tumors carciona cervis, Lewis tumor, carciona intestinum crassum were tested. After a certain time after the introduction of the fluorescein or its salts along with the other components of the agent, the animals were killed under anesthesia and the concentration of the dye in the tumor and in normal tissues was determined. The accumulation contrast was determined as the ratio of the concentrations in the malignant tissue to the normal tissue.

Bei laparoskopischen Untersuchungen wurde festgestellt, daß sich das Fluoreszein oder seine Salze in der Aszitflüssigkeit akkumulieren, was es gestattet, diese in sehr geringen Mengen zu entdecken und zum Schluß zu kommen, daß es in Organen bösartige Tiefmetastasen gibt, die visuell nicht entdeckt werden können, z.B. in der Leber, im Bauchgebiet, in der Milz u.a., was diagnostische Möglichkeiten der Laparoskopiemethode wesentlich erweitert.Laparoscopic examinations have shown that the fluorescein or its salts accumulate in the ascitic fluid, which makes it possible to detect them in very small amounts and to conclude that there are malignant deep metastases in organs that cannot be detected visually, e.g. in the liver, in the abdominal area, in the spleen, etc., which significantly extends the diagnostic possibilities of the laparoscopy method.

In den Tabellen 1 bis 4 sind Ergebnisse der Experimente auf Mäusen der Linie CBA mit dem auf den Schenkel geimpften Gebärmutterkrebs mit der Bestimmung des Akkumulierungskontrastes des Fluoreszeins in der bösartigen Geschwulst im Vergleich zum normalen Umgebungsgewebe in Abhängigkeit von der Zusammensetzung des Kontrastmittels angeführt.Tables 1 to 4 show results of the experiments on mice of the CBA line with uterine cancer vaccinated on the thigh with the determination of the accumulation contrast of the fluorescein in the malignant tumor in comparison to the normal surrounding tissue as a function of the composition of the contrast medium.

Die im Blut anwesenden bösartigen Elemente akkumulieren das Fluoreszein oder seine Salze und können nach der Fluoreszenzkontrastierung unter dem Mikroskop entdeckt werden.The malignant elements present in the blood accumulate the fluorescein or its salts and can be discovered under the microscope after the fluorescence contrasting.

Man begann mit der Untersuchung der Lokalisation des Fluoreszeins im Gewebe des Organismus nach einer bestimmten Zeit nach der Einführung des Mittels, da innerhalb dieser Zeit, der Farbstoff sich zuerst in allen Geweben gleichmäßig verbreitet und erst danach in den bösartigen Geschwulsten akkumuliert. Der Austritt aus den normalen Geweben über die Leber und die Nieren beginnt praktisch sofort nach der Einführung des Mittels. Nach einer bestimmten Zeit, die für die Lokalisation, den Typ und die Größe der bösartigen Geschwulst charakteristisch ist, wird darin eine erhöhte Konzentration des Fluoreszeins oder seiner Salze festgestellt. Die Feststellung der Lokalisation des Fluoreszeins wurde durch Fluoreszenzanalyse durchgeführt. Die Gewebe mit erhöhten und erniedrigten Konzentrationen des Fluoreszeins wurden einer histologischen Analyse zum Nachweis ihrer bösartigen Natur unterworfen.The investigation of the localization of fluorescein in the tissue of the organism began after a certain time after the introduction of the agent, since within this time the dye first spreads evenly in all tissues and only then accumulated in the malignant tumors. The exit from normal tissues via the liver and kidneys begins almost immediately after the introduction of the agent. After a certain time, which is characteristic of the location, type and size of the malignant tumor, an increased concentration of fluorescein or its salts is found. The localization of the fluorescein was determined by fluorescence analysis. The tissues with increased and decreased concentrations of fluorescein were subjected to histological analysis to demonstrate their malignant nature.

Es wurde festgestellt, daß die Richtigkeit der Diagnostik eines bösartigen Vorgangs zwecks Bestimmung der Fluoreszenz in Geweben im Vergleich zu einer üblichen histologischen Analyse eines Biopsiematerials 75 % bis 90 % in Abhängigkeit von der Lokalisation der Geschwulst beträgt.It has been found that the accuracy of the diagnosis of a malignant process to determine the fluorescence in tissues is 75% to 90%, depending on the location of the tumor, compared to a conventional histological analysis of a biopsy material.

Analoge Ergebnisse hinsichtlich der Richtigkeit der Fluoreszenzdiagnostik wurden bei klinischen Untersuchungen erzielt, wo insgesamt 350 Kranke, die am Krebs des Verdauungssystems, am Hautkrebs und am Milchdrüsenkrebs litten, untersucht.Analogous results with regard to the correctness of the fluorescence diagnosis were obtained in clinical examinations, in which a total of 350 patients suffering from cancer of the digestive system, skin cancer and breast cancer were examined.

Claims (18)

1. Contrast medium for the diagnosis of malignant growths, containing fluorescein and/or its salts as contrast substance, characterised in that it additionally contains saccharides and/or disaccharides in the following percentages by weight:
Figure imgb0029
2. Medium as claimed in claim 1, characterised in that it contains saccharides and/or disaccharides in the following percentages by weight:
Figure imgb0030
3. Contrast medium for the diagnosis of malignant growths, containing fluorescein or its salts as contrast substance, characterised in that it additionally contains vitamins in the following percentages by weight:
Figure imgb0031
4. Medium as claimed in claim 3, characterised in that it contains vitamins in the following percentages by weight:
Figure imgb0032
5. Contrast medium for the diagnosis of malignant growths, containing fluorescein or its salts as contrast substance, characterised in that it additionally contains antihistamine in the following percentages by weight:
Figure imgb0033
6. Medium as claimed in claim 5, characterised in that it contains antihistamine in the following percentages by weight:
Figure imgb0034
7. Contrast medium for the diagnosis of malignant growths, containing fluorescein or its salts as contrast substance, characterised in that it additionally contains saccharides and/or disaccharides, vitamins and antihistamine in the following percentages by weight:
Figure imgb0035
8. Medium as claimed in claim 7, characterised in that it contains saccharides and/or disaccharides, vitamins and antihistamine in the following percentages by weight:
Figure imgb0036
9. Medium as claimed in one of claims 1 to 8, characterised in that alkali metal salts are contained as fluorescein salts.
10. Medium as claimed in one of claims 1 to 8, characterised in that its ammonium salts are contained as fluorescein salts.
11. Medium as claimed in claim 9, characterised in that lithium, sodium and potassium salts are contained as salts of the alkali metal of fluorescein.
12. Medium as claimed in one of claims 1, 5 to 11, characterised in that glucose and/or fructose are contained as saccharides.
13. Medium as claimed in one of claims 1, 5 to 11, characterised in that saccharose is contained as disaccharide.
14. Medium as claimed in one of claims 3 and 7 to 13, characterised in that the vitamins of group A and/or the vitamins or group B and/or the vitamins of group C and/or P and/or PP and/or E are contained as vitamins.
15. Medium as claimed in one of claims 3 and 7 to 13, characterised in that the vitamins of group B and/or the vitamins of group C and/or P and/or PP and/or E are contained as vitamins.
16. Medium as claimed in one of claims 5 and 7 to 15, characterised in that 3-methyl-9-benzyl-1,2,4-tetrahydrocarbolin-naphthalene-1,5-disulphonate, 10-(2-dimethylaminopropyl)-phenothiazine hydrochloride, hydrochloride of N-dimethylaminoethyl-N-para-chlorobensyl)aminopyridine or of 1-methyl-2[2-(a-methylpara-chlorobenzhydryloxy)-ethyl]-pyrrolidine, 4,9-dihydro-4(1-methyl-4-piperidinylidene)-1-OH- benzo[4,5]cyclohepta(1,2]thiophene-10-OH(hydrofumarate), hydrochloride of ß-dimethylaminoethylether of benzhydrol or of quinuclydyl-3-diphenyl-carbinol are contained as antihistamine.
17. Medium as claimed in one of claims 1 to 16, characterised in that it is present as a solution or powder.
18. Medium as claimed in claim 17, characterised in that water or aqueous 5 to 30% solution of ethyl alcohol is present as solvent.
EP88117158A 1987-10-15 1988-10-14 Contrast medium for cancerous growth diagnosis Expired - Lifetime EP0312108B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SU4313068 1987-10-15
SU4313068 1987-10-15

Publications (2)

Publication Number Publication Date
EP0312108A1 EP0312108A1 (en) 1989-04-19
EP0312108B1 true EP0312108B1 (en) 1992-07-01

Family

ID=21330433

Family Applications (3)

Application Number Title Priority Date Filing Date
EP88117157A Withdrawn EP0313942A1 (en) 1987-10-15 1988-10-14 Use of fluorane derivatives and contrast medium for cancerous growth diagnosis
EP88117158A Expired - Lifetime EP0312108B1 (en) 1987-10-15 1988-10-14 Contrast medium for cancerous growth diagnosis
EP19910111514 Withdrawn EP0454185A3 (en) 1987-10-15 1988-10-14 Utilisation of fluoron derivatives as contrast agents for malignant tissues when diagnosed

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP88117157A Withdrawn EP0313942A1 (en) 1987-10-15 1988-10-14 Use of fluorane derivatives and contrast medium for cancerous growth diagnosis

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP19910111514 Withdrawn EP0454185A3 (en) 1987-10-15 1988-10-14 Utilisation of fluoron derivatives as contrast agents for malignant tissues when diagnosed

Country Status (7)

Country Link
US (1) US5093106A (en)
EP (3) EP0313942A1 (en)
JP (2) JPH01221329A (en)
BR (2) BR8805359A (en)
DE (1) DE3872481D1 (en)
FI (2) FI884721A (en)
NO (2) NO884565L (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE68927479T2 (en) * 1988-05-02 1997-04-03 Phanos Tech Inc CONNECTIONS, COMPOSITIONS AND METHOD FOR BINDING ORGANIC AFFECTION SUBSTANCES TO SURFACE MEMBRANES OF BIOPARTICLES
WO1992001478A1 (en) * 1990-07-19 1992-02-06 Charwell Pharmaceuticals Limited Diagnostic compositions for assessment of pancreatic insufficiency
EP0521568B1 (en) * 1991-07-05 1996-09-18 Tokyo Gas Co., Ltd. A low-nox gas burner
US5995645A (en) * 1993-08-18 1999-11-30 Applied Spectral Imaging Ltd. Method of cancer cell detection
US6159445A (en) * 1994-07-20 2000-12-12 Nycomed Imaging As Light imaging contrast agents
GB9502065D0 (en) * 1995-02-02 1995-03-22 Nycomed Imaging As Contrast media
US6540981B2 (en) 1997-12-04 2003-04-01 Amersham Health As Light imaging contrast agents
US5840713A (en) * 1995-04-03 1998-11-24 Weisz; Paul B. Therapy for tissue membrane insufficiency
GB9607503D0 (en) * 1996-04-11 1996-06-12 Merck Frosst Canada Inc Bisaryl cyclobutenes derivatives as cyclooxygenase inhibitors
US20040082863A1 (en) * 2002-03-15 2004-04-29 Mcgreevy James Device and method for the photodynamic diagnosis of tumor tissue
RU2235323C2 (en) * 2002-05-14 2004-08-27 Российский НИИ геронтологии Method of diagnosing malignant tumors
US7854705B2 (en) * 2004-12-16 2010-12-21 Olga Pawluczyk Ex vivo verification of biopsy tissue samples
WO2007025282A2 (en) * 2005-08-24 2007-03-01 Cedars-Sinai Medical Center Use of fructose-based compounds for the diagnosis of cancer
CA2948306A1 (en) * 2014-05-14 2015-11-19 The University Of Tokyo Enzyme-specific fluorescent compound capable of being retained in cells
CN104844674B (en) * 2015-04-30 2019-11-12 赛纳生物科技(北京)有限公司 Novel polymeric zymolyte: fluorescence can produce polyphosphoric acids end mark nucleotide and its application

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2704270A (en) * 1951-04-16 1955-03-15 Leo Ab Antihistaminic injectable X-ray contrast media
FR255F (en) * 1967-02-17
BE724644A (en) * 1967-12-07 1969-05-02
SU792878A1 (en) * 1978-08-29 1982-02-07 Ленинградский институт ядерной физики им. Б.П.Константинова Method of preparing iodine radioisotope labeled halogenated fluorescein derivatives
US4256727A (en) * 1978-09-18 1981-03-17 The University Of Kentucky Research Foundation Synthesis and use of diagnostic radio-pharmaceuticals comprising radioactive isotopes of bromine with dyes
US4401755A (en) * 1981-01-29 1983-08-30 Massachusetts Institute Of Technology Process for measuring microbiologically active material
FR2504408B1 (en) * 1981-04-24 1986-02-14 Couvreur Patrick PROCESS FOR THE PREPARATION OF SUBMICROSCOPIC PARTICLES, PARTICLES THUS OBTAINED AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US4350676A (en) * 1981-05-21 1982-09-21 Laties Alan M Ophthalmic use of carboxyfluorescein
US4820505A (en) * 1985-04-04 1989-04-11 Scripps Clinic And Research Foundation Detection of activated platelets with antibodies to thrombospondin
US4695654A (en) * 1985-08-21 1987-09-22 Merrell Dow Pharmaceuticals Inc. Gem-dihalo-1,8-diamino-4-aza-octanes
JPS6277336A (en) * 1985-10-01 1987-04-09 Nippon Sekigaisen Kogyo Kk Reagent for diagnosing cancer
US4912208A (en) * 1987-06-29 1990-03-27 Abbott Laboratories Fluorophores for encapsulation into liposomes

Also Published As

Publication number Publication date
FI884720A0 (en) 1988-10-13
BR8805359A (en) 1989-06-13
US5093106A (en) 1992-03-03
NO884565D0 (en) 1988-10-13
FI884720A (en) 1989-04-16
NO884566D0 (en) 1988-10-13
BR8805356A (en) 1989-06-13
EP0313942A1 (en) 1989-05-03
EP0312108A1 (en) 1989-04-19
FI884721A0 (en) 1988-10-13
EP0454185A2 (en) 1991-10-30
NO884565L (en) 1989-04-17
JPH01211531A (en) 1989-08-24
FI884721A (en) 1989-04-16
JPH01221329A (en) 1989-09-04
DE3872481D1 (en) 1992-08-06
EP0454185A3 (en) 1992-01-08
NO884566L (en) 1989-04-17

Similar Documents

Publication Publication Date Title
EP0312108B1 (en) Contrast medium for cancerous growth diagnosis
EP0169299B1 (en) Use of paramagnetic complex salts for the preparation of agents for nmr diagnostics
DE69533362T3 (en) Diagnostic preparation for the detection of Helicobacter pylori
DE69627170T2 (en) NON-AFFYANT REMEDIES FOR THE COLON
Fleischhauer Fluorescenzmikroskopische Untersuchungen über den Stofftransport zwischen Ventrikelliquor und Gehirn
CH642852A5 (en) MATERIAL SUITABLE FOR MARKING WITH A RADIONUCLIDE, METHOD FOR THE PRODUCTION AND USE THEREOF.
EP0131540A2 (en) Contrast agent for ultrasounds and its preparation
DE2810918A1 (en) TAURINE DERIVATIVES WITH NEUROMUSCULAR EFFECTIVENESS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS
DE202007001059U1 (en) Pharmaceutical preparation for the treatment of inflammatory diseases of the genitourinary tract
DE3050802C2 (en) Use of Rifamycin SV sodium salt in the intra-articular control of rheumatoid arthritis
CH647409A5 (en) PHARMACEUTICAL PREPARATION FOR TREATING AND PREVENTING INFLAMMABLE COLON DISEASES, SALTS OF 5,5'-AZOBISSALICYL ACID AND METHOD FOR PRODUCING THESE SALTS.
EP2005970A1 (en) Imaging diagnosis by combining contrast agents
DE2534985C2 (en)
DE3139005A1 (en) PHARMACEUTICAL PREPARATION WITH ANTI-ISCHEMIC EFFECT
EP0108820A1 (en) Infusion solutions for heart therapy
EP3237019B1 (en) Formulation of hypericin for photodynamic diagnosis
DE60216770T2 (en) IONIC AND NON-IONIC RADIOGRAPHIC CONTRASTIVE FOR USE IN COMBINED ROENTGEN AND NUCLEAR PNPOMAGRAPHY DIAGNOSTICS
DE60026743T2 (en) Use of contrast agents for the preparation of a diagnostic agent for intestinal lumen imaging
CH641682A5 (en) X-ray contrast medium
DE69630639T2 (en) Rhodamine 123 compositions for prostate cancer treatment
EP2598174B1 (en) Measurement method for determining an organ function
DE3724188C2 (en) Metal-containing oligosaccharide polysulfates, process for their preparation and pharmaceutical compositions containing them
DE2419310C3 (en) Use of Tc-99m complexes
DE1805257A1 (en) Diagnostic preparation and process for its manufacture
DE1932231A1 (en) Diagnostic and therapeutic preparation based on a chelate-bound radio-nuclide

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19881228

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): CH DE FR GB IT LI SE

17Q First examination report despatched

Effective date: 19901204

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BIO-PHOTONICS GMBH

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BIO-PHOTONICS, INC.

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

ITF It: translation for a ep patent filed

Owner name: TOP - PATENTS - ITALO INCOLLINGO

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): CH DE FR GB IT LI SE

REF Corresponds to:

Ref document number: 3872481

Country of ref document: DE

Date of ref document: 19920806

ET Fr: translation filed
GBT Gb: translation of ep patent filed (gb section 77(6)(a)/1977)
PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19940330

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19941013

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19941018

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19941024

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19941027

Year of fee payment: 7

EAL Se: european patent in force in sweden

Ref document number: 88117158.1

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19950701

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19951014

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19951015

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Effective date: 19951031

Ref country code: CH

Effective date: 19951031

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19951014

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Effective date: 19960628

EUG Se: european patent has lapsed

Ref document number: 88117158.1

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20051014